Citations

Background/Objectives: Tumor-infiltrating lymphocyte (TIL) therapy is an important option for patients with metastatic melanoma progressing after standard systemic therapy, but real-world data on treatment delivery, toxicity monitoring, and immune recovery remain limited. We evaluated clinical outcomes, treatment tolerance, immune reconstitution, and cardiac biomarker dynamics across three Mayo Clinic sites. Methods: We retrospectively analyzed adults with metastatic melanoma who received lymphodepleting chemotherapy followed by TIL infusion and high-dose interleukin-2 (IL-2) between April 2024 and December 2025. Clinical outcomes, treatment delivery, and adverse events were assessed. Longitudinal immune monitoring included CD4 and CD8 T-cell counts, CD4:CD8 ratio, and immunoglobulin G (IgG) at baseline and follow-up. In a prespecified cardiac sub-cohort, high-sensitivity troponin (hs-Tn) was measured during IL-2 administration to evaluate associations with cardiac events and IL-2 interruption. Results: Thirty-six patients underwent TIL infusion. The objective response rate was 50.0%, including complete responses in 13.9%, and the disease control rate was 72.2%. Median progression-free survival was 3.61 months, and median overall survival was 12.94 months. M1d disease was associated with inferior overall survival on univariable analysis (HR 6.55, 95% CI 2.03–21.17; p = 0.002), with attenuation after multivariable adjustment. Receipt of ≥3 IL-2 doses was associated with longer overall survival on univariable analysis (HR 0.20, 95% CI 0.06–0.64; p = 0.007), but this association also attenuated after adjustment. Longitudinal immune monitoring demonstrated persistent CD4 lymphopenia through 6 months, sustained inversion of the CD4:CD8 ratio, and declining IgG at months 3 and 6. In the cardiac sub-cohort (24 patients; 87 IL-2 doses), post-dose hs-Tn ≥15 ng/L was associated with clinically significant cardiac events (OR 9.6, 95% CI 1.5–60.6; p = 0.016) and IL-2 interruption (OR 3.4, 95% CI 1.1–10.7; p = 0.036). For cardiac events, hs-Tn ≥15 ng/L had 100% sensitivity and 100% negative predictive value. Conclusions: In routine practice, TIL therapy was feasible and active in metastatic melanoma. M1d disease identified a subgroup with poor survival, peri-dose hs-Tn showed promise as a tool to support safer IL-2 delivery, and prolonged CD4 suppression with IgG decline suggests that recovery after TIL therapy extends beyond initial hematologic reconstitution. These findings support prospective validation of biomarker-guided IL-2 monitoring and extended post-treatment immune surveillance.

Ex vivo liver perfusion (EVLP) sustains human or large animal livers outside the body under near-physiological conditions, enabling functional monitoring for lactate clearance, bile production, and oxygen consumption and allowing targeted therapeutic interventions. Originally developed to optimize donor grafts for transplantation, EVLP has evolved into a powerful translational research platform bridging preclinical discovery and early clinical translation. This review discusses EVLP as a platform for gene therapy, immunotherapy, pharmacology, and personalized medicine, with particular emphasis on gene- and immune-based interventions as mechanistically mature exemplars. We consolidate advances in pharmacological testing and toxicity modeling, viral and non-viral gene delivery, genome engineering, and immunomodulation using perfused livers. We further describe emerging applications, including autologous EVLP pathways for organ-confined therapy, ex vivo liver surgery, and bioengineering strategies such as biliary organoid repair, RNA interference, and mitochondrial transfer. We highlight how these applications align with a paradigm shift in biomedical research, including the NIH’s recent initiative to prioritize human-based experimental models over animal-only studies. By leveraging transplant-declined or surgically resected organs that would otherwise be unused, ex vivo perfusion bridges the gap between pre-clinical testing and clinical practice, enabling real-time evaluation of interventions in functional human tissue. We discuss both the scientific opportunities afforded by EVLP and the technical, biosafety, and ethical challenges that must be addressed to enable responsible clinical translation.

Background/Objectives: Cardiovascular disease (CVD) burden decreased in the North Africa and Middle East (NAME) region between 1990 and 2019. This study used Global Burden of Disease (GBD) 2023 data to examine whether trends in mortality, disability-adjusted life years (DALYs), incidence, and prevalence continued through 2023 across all 21 NAME countries. Methods: We analysed age-standardised CVD mortality, incidence, prevalence, and DALY rates from 1990 to 2023. Joinpoint regression identified changes in temporal trends and calculated the annual percent change (APC) and average annual percent change (AAPC) with 95% confidence intervals (CIs). Results: Age-standardised CVD mortality decreased from 579.6 per 100,000 in 1990 to 358.2 in 2023 (AAPC: −1.42%; 95% CI: −1.48 to −1.35). However, no significant reduction occurred between 2019 and 2023 (APC: −0.33%; 95% CI: −1.37 to 1.75). DALY, incidence, and prevalence rates followed similar patterns, with no significant decline in the final years of this study. Egypt was the only country with a long-term increase in CVD mortality, which accelerated after 2020 (APC: +5.20%; 95% CI: 1.20 to 12.87). High systolic blood pressure, dietary risks, lead exposure, and air pollution were the leading modifiable risk factors. Conclusions: The earlier decline in CVD burden in the NAME region did not clearly continue after 2019. The region is currently off track to meet Sustainable Development Goal 3.4 by 2030. Future progress may depend on improved blood pressure control, lipid management, dietary habits, and environmental risk reduction.

130 Background: The COVID-19 pandemic markedly affected the U.S. health care system and may have altered the diagnosis and management of pancreatic cancer. We examined national trends in pancreatic cancer diagnoses before and throughout the first two years after the onset of COVID-19 in the United States, using the latest data from the Surveillance, Epidemiology, and End Results (SEER) database. Methods: We queried the SEER database for cases of pancreatic cancer diagnosed between 2019 and 2021 using ICD-O-3 codes C25.0-C25.9. Disease stage was categorised as localised, regional, distant, or unknown according to the SEER combined summary staging system. Case counts and incidence rates were compared across 2019, 2020, and 2021, with year-to-year differences assessed for statistical significance using χ² tests. Results: The overall number of cases of PDAC diagnosed in 2019, 2020, and 2021 (including year-to-year changes) were 13,457, 13,153 (-2.3%, p<0.05), and 13,998 (+6.4%, p<0.001). Among the known SEER summary staging for PDAC, 52.3% of cases were categorised as “distant” at the time of diagnosis in 2019, compared to 53.6% (+2.4%, p<0.05) in 2020, and 52.0% (-2.8%, p<0.05) in 2021. This reflected an overall change of -0.5% in “distant” PDAC diagnoses from 2019 to 2021 (p>0.05). Conclusions: Significantly fewer cases of PDAC were diagnosed in 2020 compared with 2019, followed by a significant increase in 2021 to above pre-pandemic levels. The proportion diagnosed as distant was significantly higher in 2020 than in 2019 but did not differ significantly between 2019 and 2021. These findings suggest a transient shift toward more advanced-stage PDAC diagnoses during the first year of the COVID-19 pandemic with likely delays in diagnosis, which returned to baseline in 2021.

129 Background: Pancreatic ductal adenocarcinoma (PDAC) presents with significant morbidity and mortality. Five-year survival at 13% consistently remains among the lowest of all cancers. We undertook a population-level risk analysis of sociodemographic risk factors (sex, age, ethnic, and geographic) that may inform closer monitoring of those with increased likelihood of developing PDAC. Methods: PDAC incidence data from 2000 to 2022 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database, representing approximately 37% of the US population. Age-adjusted incidence rates (AAIRs) were calculated by race, sex, age group, and county-level rural–urban classification. Incidence is reported per 100,000 population. Temporal trends were assessed using annual percent change (APC) estimated via weighted least-squares regression. Results: Between 2000 and 2022, the overall AAIR of PDAC was 12.6. Incidence was highest among Black individuals (16.1), followed by White (12.7) and Hispanic (11.7) individuals, and was consistently higher in males (14.3) than in females (11.2). Temporal trends did not differ significantly by sex, with annual increases of +0.8% in males and +0.9% in females. Incidence increased progressively with age across all racial and ethnic groups in both sexes. While overall incidence was comparable between urban and rural counties, rural counties experienced a significantly faster rise in incidence (+1.3% vs. +0.8% APC; p<0.05). Conclusions: PDAC incidence has increased from 2000 to 2022 across both sexes at all ages and across all ethnicities. Those most at risk include males and Black individuals, with rates rising faster in rural counties. Better epidemiological understanding of developing trends of at-risk patients may inform screening strategies for patients at high risk of developing PDAC. Incidence rate (per 100,000 population) and annual change in PDAC (95% CI with Tiwari modification). Rate Trend Sex Male 14.3 (14.2-14.4) 0.8 (0.7-0.9) Female 11.2 (11.1-11.3) 0.9 (0.8-1.0) Age 40-44 years 2.7 (2.6-2.8) 1.3 (0.8-1.8) 45-49 years 5.6 (5.4-5.8) 0.8 (0.5-1.1) 50-54 years 10.9 (10.8-11.1) 0.6 (0.4-0.9) 55-59 years 19.2 (19.0-19.5) 1.0 (0.7-1.3) 60-64 years 30.8 (30.0-31.1) 0.8 (0.5-1.0) 65-69 years 45.9 (45.0-46.4) 0.9 (0.7-1.0) 70-74 years 62.2 (62.0-62.8) 0.8 (0.6-0.9) 75-79 years 79.7 (79.0-80.6) 1.0 (0.8-1.2) 80-84 years 94.7 (94.0-95.8) 0.9 (0.7-1.1) 85-89 years 104.6 (103-106.1) 0.8 (0.5-1.1) 90+ years 101.7 (100-103.6) 0.4 (0.1-0.8) Race White 12.7 (12.6-12.8) 1.1 (1.0-1.2) Black 16.1 (16-16.3) 0.3 (0.2-0.5) American Indian/Alaska Native 10.5 (10.0-11.1) 1.4 (0.4-2.4) Asian or Pacific Islander 10.2 (10.0-10.4) 0.6 (0.4-0.8) Hispanic 11.7 (11.5-11.8) 0.7 (0.4-0.9) Location Urban 12.6 (12.5-12.7) 0.8 (0.7-0.9) Rural 12.6 (12-12.7) 1.3 (1-1.5)

Abstract Myelodysplastic syndromes (MDS) are clinically and biologically diverse disorders, emphasizing the need for personalized treatment approaches. The International Working Group for Prognostication of MDS (IWG_PM) recently introduced a molecular classification, referred to as the MDS taxonomy, that categorizes patients into 16 subgroups based on 21 gene mutations, 6 cytogenetic abnormalities, and loss of heterozygosity (LOH) at TP53 and TET2 loci. This study sought to validate and enhance the clinical relevance of the MDS taxonomy by analyzing a large retrospective cohort ( n = 5136) and transcriptomic data from a prospective cohort ( n = 477). The taxonomy successfully identified subgroups with distinct clinical characteristics and disease progression patterns. However, incorporating gene interactions from taxonomy subgroups did not improve the prognostic performance of the Molecular International Prognostic Scoring System (IPSS‐M). We further assessed whether the taxonomy could guide management in patients receiving disease‐modifying therapies. Except for the “ TP53 ‐complex” subgroup, taxonomy classifications were not predictive of hypomethylating agent response or transplant outcomes. Nonetheless, they correlated with overall survival, suggesting that while both IPSS‐M and the taxonomy capture disease biology, other non‐genetic factors may influence treatment response. RNA sequencing confirmed the biological distinctiveness of the taxonomy groups. Transcriptomic profiling of CD34+ bone marrow cells revealed unique, homogeneous gene expression patterns, particularly within the AML‐like, bi TET2 , SF3B1 , and TP53 ‐complex subgroups. Further integration of multi‐omics data may refine MDS classification, improving clinical decision‐making and guiding the development of targeted therapies.

Abstract Purpose: To explore the potential of the metaverse, a three-dimensional platform merging physical and virtual realities (VRs), in advancing the field of ophthalmology. This study examines its applications in areas such as VR-based surgical training, augmented reality (AR)-assisted surgeries, artificial intelligence (AI)-driven diagnostics, and teleophthalmology. This review builds upon previous literature by integrating recent evidence and technological advancements, offering a more comprehensive analysis of particular applications and barriers in ophthalmology. Methods: Academic literature published between 2019 and 2024 was identified through searches in the PubMed database and Google Scholar search engine using relevant keywords. This review focused on studies discussing the application of the metaverse in health care and ophthalmology, with particular attention to key trends, emerging uses, technological features, and associated challenges. Results: A total of 60 studies were deemed relevant for inclusion in this review. The infrastructure supporting the Metaverse comprises technologies such as the Internet of Things, digital twins, mirror worlds, nonfungible tokens, blockchain technology, and lifelogging. Together, these technologies create immersive environments that users can access through VR headsets, AR glasses, and handheld controllers. The metaverse presents promising opportunities in ophthalmology, particularly in enhancing clinical training through simulators such as the EyeSi™ surgical simulator, VRmagic EyeSi Slit Lamp, and the HelpMeSee™ VR simulator. In addition, it facilitates remote consultations and improves diagnostic and treatment options, exemplified by tools such as the Vivid Vision™ system for amblyopia, the Microsoft HoloLens™ for navigating complex anatomical structures, and AI-based platforms for the early detection of diseases such as glaucoma and diabetic retinopathy. Furthermore, the metaverse may enhance patient education by simulating the visual effects of ophthalmic conditions and visualizing postoperative outcomes. However, challenges, including financial limitations, data security concerns, and cultural acceptance, must be addressed. Conclusions: A gradual and context-specific integration of the metaverse is essential, particularly in underdeveloped regions. As the metaverse evolves, it holds significant potential to transform the field of ophthalmology by promoting global collaboration and innovation, complementing traditional practices, and ensuring equitable access to advanced healthcare solutions.